Comparison of auranofin,gold sodium thiomalate,and placebo in the treatment of rheumatoid arthritis

A prospective controlled, double-blind multi-center trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombo-cytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, “nitritoid” reactions, and “gold pneumonitis” were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.     

Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial

A prospective controlled, double-blind multicenter trial compared placebo, auranofin (an orally administered gold complex), and parenteral gold sodium thiomalate (GST) in patients with active rheumatoid arthritis (RA). Of 193 patients who received any treatment, the only important improvement identified for either auranofin or GST was for pain/tenderness scores. When 161 patients who completed 20 weeks of treatment were examined, both auranofin and GST treatments were superior to placebo as measured by improvement in number of painful and/or tender joints, joint pain/tenderness scores, physician's assessment of disease activity, and decrease in erythrocyte sedimentation rate when elevated at entry. GST was superior to placebo in improvement of joint swelling scores, anemia, thrombocytosis, and rheumatoid factor. No drug-related remissions were observed. The only statistically significant advantages of GST over auranofin for efficacy were an increase in hemoglobin concentration and decrease of thrombocytosis with GST. Withdrawals for adverse effects were 5 times more frequent with GST treatment. Thrombocytopenia, proteinuria, elevated liver enzymes, "nitritoid" reactions, and "gold pneumonitis" were observed only in the GST treatment group. These results confirm that both parenteral and oral gold may be effective for the treatment of RA, that GST tends to show greater efficacy than auranofin, and that auranofin has fewer significant adverse effects than GST. However, long-term benefits, tolerability, and safety cannot be inferred from this study.     

Serum gold concentrations during treatment with auranofin

Summary Serum gold concentrations were measured in rheumatoid arthritis patients during chronic treatment with the orally absorbable gold compound auranofin. In agreement with data in the literature, the highest serum gold concentration was reached after 16 weeks of treatment with 6 mg auranofin daily. A striking finding in this study was that thereafter the serum gold concentrations did not appear to plateau but declined gradually. Statistically this resulted in a significantly lower concentration after one year as compared with week 16 (p<0.05, paired t-test). It is suggested that a shift from protein bound gold to cell-bound gold might be the explanation.     

Effects of auranofin and myochrysine on intestinal transport and morphology in the rat.

Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible mechanism for this we compared the effects of auranofin and myochrysine on intestinal water and solute transport in the rat. Jejunal perfusion with 2 mM auranofin (n = 5) induced fluid and electrolyte secretion and inhibited glucose absorption (p less than 0.01). Auranofin (0.2 mM) induced fluid secretion in the jejunum (n = 5; p less than 0.01) and colon (n = 6; p less than 0.01). In contrast, 2 mM myochrysine enhanced jejunal water and electrolyte absorption (n = 6; p less than 0.02). Both compounds enhanced absorption of mannitol (p less than 0.01). Perfusion of 0.2 mM auranofin for two hours had no significant effect on mucosal c-AMP levels (n = 4). After perfusion for two hours with 2 mM auranofin the jejunal mucosa showed severe injury by light and scanning electronmicroscopy while myochrysine had no apparent effect. The damage after perfusion with 0.2 mM auranofin for two hours was less severe. Auranofin was more rapidly absorbed than myochrysine (p less than 0.05). These effects provide an explanation for the diarrhoea associated with auranofin therapy.     

Blood gold concentrations in children with juvenile rheumatoid arthritis undergoing long-term oral gold therapy.

During an uncontrolled, open-labelled, open-ended clinical trial of auranofin in children with juvenile rheumatoid arthritis (JRA) we obtained serial blood samples for the purpose of assessing gold content. Our objectives were (1) to observe the pattern of blood gold concentrations over a period of time in children undergoing long-term oral gold therapy, and (2) to observe the effect of changing dosage levels on blood gold concentrations. The initial dosage of auranofin was 0.1 mg/kg/day with allowable increases to 0.2 mg/kg/day. A concurrent nonsteroidal anti-inflammatory drug was allowed. Twenty-one patients were enrolled in the study, and we obtained 2 or more serial samples on 13 of the children. At a constant dosage of 0.1 mg/kg/day, steady state blood gold concentrations were attained in 11 to 13 weeks of therapy and, in the absence of a dosage change, remained remarkably constant through extended periods. The blood gold concentration was related to total daily dosage rather than to the cumulative amount of gold received. Increasing or decreasing the dose resulted in a direct effect on concentration. The clinical value of blood gold levels resulting from auranofin therapy in JRA will have to be established through double-blind controlled trials.     

Auranofin: A unique oral chrysotherapeutic agent

Auranofin is a chemically unique gold coordination complex with demonstrated antiarthritic properties on oral administration. Its pharmacokinetic and immunologic profiles are distinct from injectable gold compounds.When auranofin is added to a regimen of salicylates and/or a nonsteroidal antiinflammatory drug for the treatment of RA, significant additional therapeutic benefit is observed. Published studies indicate that auranofin given 6 mg per day approaches the efficacy of parenteral gold salts in the treatment of rheumatoid disease. Noticeable improvement in clinical and laboratory parameters of disease activity has been observed by the third month of auranofin therapy. Further benefit occurs in some patients during the remainder of the first year of treatment.In the more than 3,000 patients treated with auranofin, the most frequently reported side effects were gastrointestinal (mainly diarrhea) and mucocutaneous. Most side effects were mild in nature and the withdrawal rate due to all adverse reactions averaged 11%.Auranofin differs from injectable gold by producing more gastrointestinal but fewer mucocutaneous reactions. The severity of these reactions is less with auranofin and causes fewer withdrawals from therapy.     

Characterization of the in vitro effect of triethylphosphine gold (auranofin) on human NK cell activity

Pharmacological concentrations of auranofin (oral gold) modulated NK cell activity in a dose dependent biphasic manner. In vitro low doses enhanced NK cell activity, while high doses inhibited the NK cell activity. Sodium aurothiomalate (parenteral gold) had no effect. The effect of auranofin on NK cell function was irreversible and independent of the presence of monocytes. Neither IF nor Il-2 abolished the auranofin-suppressed NK cell activity. When NK cell activity was enhanced by low doses of auranofin, both IF and Il-2 could further boost the NK cell function. Using percoll fractionated NK cell enriched populations in a single cell agarose assays, it was shown that auranofin did not influence effector/target cell conjugate formation. The effect of auranofin on NK cell activity is thus due to an influence on the lytic step.     

Gold levels produced by treatment with auranofin and sodium aurothiomalate.

Sixty-three patients with rheumatoid arthritis were randomly divided into 3 groups, and treated with either sodium aurothiomalate (Myocrisin), auranofin, or placebo. Gold levels in whole blood, plasma, and haemolysate were measured serially along with clinical and laboratory parameters of efficacy. Auranofin produced a higher ratio of haemolysate to plasma gold than Myocrisin, and it appears that the affinity of the red cell for gold is reduced during therapy with auranofin. Gold levels did not correlate with changes in the pain score, erythrocyte sedimentation rate, and C-reactive protein, nor with the development of toxicity. In the Myocrisin group the haemolysate gold level achieved was dependent on the number of cigarettes smoked. In the auranofin group there was no such correlation, but the haemolysate gold level was higher for smokers than non-smokers. The likely action of gold is discussed.     

Pharmacokinetics of gold following administration of auranofin (SK+FD-39162) and myochrysine to rats

Auranofin orally administered to rats resulted in delayed and protracted peak blood and serum gold levels occurring 24 to 48 h post administration. During this period, the gold concentration in blood was higher than in serum indicating that a major portion of gold was associated with the cellular components. During 1st order elimination (greater than 48 h), the blood/serum gold ratio decreased which suggested dissociation of cellular gold. Biliary cannulation experiments demonstrated that the protracted gold levels (24 to 48 h) could not be due to hepatic recirculation. In contrast to auranofin, gold sodium thiomalate produced blood gold levels which peaked within 3 h, rapidly declined and were consistently lower than serum gold levels.     

Treatment of psoriatic arthritis with auranofin and gold sodium thiomalate

Summary Forty-two patients with psoriatic arthritis were included in a multicenter, double-blind trial comparing auranofin and gold sodium thiomalate (GST) for 6 months, followed by a 6-month open treatment. Fifty-two percent of the patients on auranofin and 33% on GST were able to complete the 1-year course of therapy. As a result of the study we conclude that both gold compounds are effective agents in the treatment of psoriatic arthritis. Degree of improvement of arthritis was better in the GST group, but the number of improved patients was greater in the auranofin group. Two patients on auranofin were withdrawn for side effects (one diarrhoea, one worsening of psoriasis) and 5 on GST (rash 2, total loss of appetite 1, exacerbation of psoriasis 2). Comparing the side effects of both compounds, auranofin is less likely to aggravate the psoriatic condition or result in withdrawal of patients for adverse reactions.     

Gold, nitritoid reactions and angiotensin-converting enzyme inhibitors

SIR, Vasomotor or nitritoid reactions are well-recognized reactionsoccurring in approximately 5% of patients treated with gold[1]. Patients may experience facial flushing, nausea, vomiting,hypotension or syncope. Serious sequelae have been reported,including myocardial infarction (MI) [2]. The reactions aremost commonly associated with gold sodium aurothiomalate (myocrisin)but have been reported with oral gold (auranofin) [3]. The reactionsare usually transient, occurring within a few minutes of drugadministration and most within the first year of treatment,although late reactions have been reported rarely [     

A MULTICENTRE DOUBLE-BLIND COMPARISON OF AURANOFIN, INTRAMUSCULAR GOLD THIOMALATE AND PLACEBO IN PATIENTS WITH PSORIATIC ARTHRITIS

The efficacy and safety of the oral gold compound auranofinand intramuscular gold thiomalate have been compared in a placebo-controlled,double-blind, four-centre trial in 82 patients with psoriaticarthritis requiring remittive drug therapy. There were statisticallysignificant falls in Ritchie articular index, visual analoguepain score and ESR at 12 and 24 weeks following i.m. gold butno significant changes in the auranofin group. Intramusculargold was safe and more effective than auranofin as a second-line,suppressive antirheumatic agent for patients with psoriaticarthritis when followed for 6 months. KEY WORDS: Second-line treatment, Oral gold, Toxicity, Effectiveness     

Biliary, renal and fecal elimination and distribution of gold after a single oral administration of auranofin, quantified by the instrumental neutron activation analysis method

Three days after cholecystectomy, seven patients received a single dose of auranofin (5 tablets Ridaura = 4.35 mg gold). At defined time points thereafter the gold content in samples of blood, plasma, urine, bile, and feces was determined by instrumental neutron activation analysis (INAA). Maxima of the mean gold concentrations in blood (140 +/- 42 ng/ml) and plasma (173 +/- 54 ng/ml) are found 2 h after oral administration of the antirheumatic agent, after 16 h in urine (43 +/- 28 ng/ml) and bile (65 +/- 50 ng/ml), and after 24 h in erythrocytes (greater than 200 ng/ml). The mean terminal half-lives are 7.6 days (blood), 15 days (plasma), 5 days (erythrocytes), and 6.5 days (bile). The cumulative biliary gold excretion within 8 days after the administration of auranofin was 1.6%, compared with 4% and 40% for renal and fecal elimination, respectively. The gold concentration in plasma is always higher than that in bile. There is a close correlation between the areas under the concentration curves (AUC) in bile and plasma (r = 0.864).     

Effect of auranofin on DNA and protein synthesis in human lymphocytes.

The effect of auranofin-a new oral gold compound for the treatment of rheumatoid arthritis-and gold sodium thiosulphate on DNA and protein synthesis, as well as their effect on membrane transport in stimulated lymphocytes was studied. It was found that only auranofin in the given concentrations inhibits the incorporation of 3H thymidine and 14C amino acids. The studies on membrane transport present evidence that the pharmacological action of auranofin might be mediated through its action at the cellular membrane level.     

Pityriasis rosea and discoid eczema: dose related reactions to treatment with gold.

Sixteen cases of either a pityriasiform or discoid eczematous rash occurring in patients with rheumatoid arthritis receiving treatment with gold (sodium aurothiomalate and auranofin) were studied. The results suggest that this is a dose related, not allergic, reaction to gold. The development of this rash is not an absolute indication to stop treatment with gold. Control can often be effected with potent topical steroids or a reduction in the dose or frequency of treatment with gold.     

Mucosal metabolism in ulcerative colitis and crohn's disease

PURPOSE: Colonic mucosal metabolism of butyrate may be impaired in ulcerative colitis. In this study we sought to confirm this observation, to determine if a similar change occurs in Crohn's colitis, and to establish whether a panenteric disorder of butyrate metabolism exists in either condition. METHODS: With use of a microculture technique, mucosal metabolic fluxes of¹⁴[C]-labeled butyrate and¹⁴[C]-labeled glutamine were measured as¹⁴[C] carbon dioxide production in mucosal biopsy specimens from the colon and ileum in patients with ulcerative colitis, Crohn's colitis, and healthy bowel. Results were expressed as pmol/µg biopsy DNA/hour. RESULTS: In the colon the mucosal metabolic fluxes of both butyrate and glutamine are reduced in both ulcerative colitis and Crohn's colitis compared with healthy controls. These changes were most marked in the presence of moderate to severe mucosal inflammation, there being no significant difference in mucosal metabolic flux between mildly inflamed mucosa and healthy controls. In the ileum the mucosal metabolic fluxes of butyrate and glutamine did not differ between healthy controls and those with either ulcerative colitis or Crohn's colitis. CONCLUSIONS: Changes in colonic mucosal metabolism of butyrate and glutamine in inflammatory bowel disease occur as a consequence of the inflammatory process and are not peculiar to ulcerative colitis. Ileal mucosal metabolism is unchanged in ulcerative colitis and Crohn's colitis, indicating the absence of a panenteric abnormality of mucosal metabolism in these two conditions.Supported by the Mater College, Dublin, Ireland.Portions of this work were read at the American Gastroenterological Association San Francisco, California, May 19 to 24, 1996, and an abstract was published in Gastroenterology 1996;110:A900.     

Auranofin: an oral chrysotherapeutic agent for the treatment of rheumatoid arthritis

Auranofin, an oral chrysotherapeutic agent, administered at 3.0 mg. b.i.d., p.o. to eight rheumatoid arthritic patients produced improvement in objective and subjective clinical signs, as well as biochemical and immunological parameters. Adverse effects reported were minimal and generally limited to gastrointestinal disturbances. During auranofin administration, gold concentrations in the blood gradually increased to a mean level of 0.70 microgram Au/ml by week 12 of treatment. Daily oral administration of auranofin appears to provide constant blood gold levels over longer periods of time compared to existing parenteral gold therapy and may provide an improved method of controlling chrysotherapy in rheumatoid arthritic patients.     

A double blind multicentre study of OM-8980 and auranofin in rheumatoid arthritis.

The therapeutic efficacy of the immunomodulator OM-8980 in rheumatoid arthritis was compared with that of auranofin, an oral gold salt, in a double blind, randomised multicentre study lasting six months. Seventy patients were treated with auranofin and 75 with OM-8980. The patients of both groups improved significantly at three and six months for all the clinical parameters observed: Ritchie index, number of swollen joints, morning stiffness, pain, grip strength, intake of non-steroidal anti-inflammatory drugs, and erythrocyte sedimentation rate. No serious side effects were observed in either group. The patients receiving auranofin had more adverse reactions, mainly affecting the gastrointestinal system.     

Studies of the intestinal metabolism of oral gold

In order to understand some of the unique toxic/therapeutic properties of the orally administered gold containing compound auranofin, the intestinal metabolism of gold was studied in 4 normal subjects. A triple lumen intestinal perfusion apparatus was used to measure intestinal flux using a non-absorbable radiolabelled marker dilution technique. Over a short (50 cm) segment of proximal small bowel, substantial disappearance of gold was observed; the findings, however, were most consistent with a loose, reversible adsorption onto the enteric cell surface rather than true trans-mucosal absorption. There was no evidence for an entero-hepatic recirculation of gold in these subjects or in 4 additional patients with rheumatoid arthritis studied in a similar manner.     

Effect of oral gold salt therapy on bile acid absorption in rheumatoid arthritis patients

Summary Several studies pointed out an altered stool pattern as the most common side effect of auranofin therapy. The major mechanism in the aetiology of auranofin-induced impairment in bowel habit seems to be the inhibition of Na⁺/K⁺ A TPase in the gut. In vitro experiments proved that auranofin can affect active bile acid (BA) reabsorption in rat terminal ileum; this action, due to the ability of the drug to reduce Na⁺ pump activity by inhibiting Na⁺/K⁺ATPase, may make a significant contribution to the auranofininduced diarrhoea. The ability of auranof in to reduce the Na⁺ gradient necessary for active BA reabsorption, however, could cause a decrease of serum BA levels in patients taking auranofin before or without the development of an overt diarrhoea. We measured fasting and postprandial serum conjugated BA levels in 10 female rheumatoid arthritis patients before and after one month and two months' auranofin treatment. No patient developed diarrhoea during the chrysotherapy. When oral gold salt therapy was started, we observed a slight decrease in serum BA levels, but difference was not statistically significant. We can conclude that auranofin therapy does not cause BA malabsorption in patients who do not develop diarrhoea during the treatment.